Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232

Fc gamma RIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of Fc gamma RIIB, Fc gamma RIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of Fc gamma RIIB- T232 at both functional and structural levels. Our results showed that Fc gamma RIIB-T232 exhibited significantly reduced lateral mobility compared with Fc gamma RIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for Fc gamma RIIB-T232 to diffuse and interact with the ICs, Fc gamma RIIB-T232 can restore its inhibitory function. Moreover, substituting the Fc gamma RIIB-T232 TM domain with that of a fast floating CD86 molecule restored both the rapid mobility and the inhibitory function, which further corroborated the importance of fast mobility for Fc gamma RIIB to function. Mechanistically, the crippled lateral mobility of Fc gamma RIIB-T232 can be explained by the structural changes of the TM domain. Both atomistic simulations and nuclear magnetic resonance measurement indicated that the TM helix of Fc gamma RIIB-T232 exhibited a more inclined orientation than that of Fc gamma RIIB-I232, thus resulting in a longer region embedded in the membrane. Therefore, we conclude that the single-residue polymorphism T232 enforces the inclination of the TM domain and thereby reduces the lateral mobility and inhibitory functions of Fc gamma RIIB.